Bis-imidazolyl-bisphenylmethane and salts thereof as antifungal agents

ABSTRACT

BIS-IMIDAZOLYL-BISPHENYLMETHANE ANDPHARMACEUTICALLY ACCEOPTABLE NON-TOXIC SALTS THEREOF ARE USEFUL AS ANTIMYCOTICS ESPECIALLY AGAINST DERMATOMYCOSIS CAUSED BY TRICHOPHYTON AND MICROSPORIUM SPECIES AND ALSO AGAINST YEAST INFECTIONS OF THE SKIN AND INTERNAL ORGANS.

United States Patent Olfice 3,824,310. Patented July 16, 1974 US. Cl. 424-273 65 Claims ABSTRACT OF THE DISCLOSURE Bis-imidazolyl-bisphenylmethane and pharmaceutically acceptable non-toxic salts thereof are useful as antimycotics especially against dermatomycosis caused by Trichophyton and Microsporium species and also against yeast infections of the skin and internal organs.

This is a division of application Ser. No. 873,098, filed Oct. 31, 1969.

The present invention is concerned with bis-imidazolylbisphenylmethanes, salts thereof, processes for their production, pharmaceutical compositions containing such compounds and methods of treating fungal infections pathogenic to humans and animals and methods of treating yeast infections pathogenic to humans and animals. More particularly, the compounds of the present invention are bis-imidazolyl-bisphenylmethanes which may be substituted in one or both of the imidazolyl moieties and one or both of the phenyl moieties.

The compounds of the present invention are particularly useful as antimycotics especially against dermatomycosis caused by Trichophyton and Microsporium species and also against yeast infections of the skin and internal organs.

The compounds of the present invention may be represented by the formula:

mis0,lor2, nis0,1or2,

wherein and includes salts of such compounds.

When R R or R is alkyl, it is preferred that the alkyl moiety contain from 1 to 4 carbon atoms. When it is aryl, it is preferred that the aryl moiety contain up to carbon atoms in the ring system and the preferred aryl moiety is phenyl. The aryl may be substituted in which event the preferred substituents are lower alkyl, S-alkyl or alkoxy, haloalkyl of 1 to 4 carbon atoms in the alkyl portion and preferably 1 or 2 carbon atoms in the alkyl portion and wherein the halogen is preferably fluorine, chlorine or bromine, or by an electronegative moiety, preferably a halogen.

When X or Y is alkyl, it is preferred that the alkyl moiety contain from 1 to 12 carbon atoms and preferably 1 to 4 carbon atoms. When it is S-alkyl or alkoxy, it is preferred that the alkyl portions contain from 1 to 4 carbon atoms. When it is an electronegative moiety, it is preferred that the electronegative moiety be halogen, i.e. fluorine, chlorine, bromine or iodine, N0 CR, or CN.

It is to be appreciated that when X or Y is more than one such moiety as above defined, such as in the case where m or n is 2, that the moieties may be the same or different.

The term alkyl includes straight chain and branched chain alkyl moieties a swell as the saturated alkyl moieties and the partially unsaturated moieties, i.e. those containing a double bond.

The salts of the bis-imidazolyl-bisphenylmethanes of the present invention are preferably pharmaceutically acceptable non-toxic salts and examples of acids which give salts useful as hereinabove discussed include the halogen hydracids, phosphoric acid, monoand bifunctional carboxylic acids and hydroxycarboxylic acids, for example, acetic acid, propionic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid and l,5-naphthalene'di-sulphonic acid. Of particular interest are the hydlrohalides, particularly the chlorides, lactates and salicylates of the bis-imidazolylbisphenylmethanes.

According to a preferred embodiment of the present invention, R R and R are hydrogen, X and Y are the same or different and are fluorine, chlorine, bromine, iodine, CN, N0 methoxy, thiomethyl or CF and m and n are l.

The bis-imidazolyl-bisphenylmethanes of the present invention may be produced by reacting a diphenyl-dihalomethane of the formula:

Eel

Xm Hal Yn wherein X, Y, m and n are as above defined and wherein Hal is chlorine, bromine or iodine, with the stoichiometric amount of and imidazole derivative of the formula:

wherein R R and R are as above defined, in the presence of an inert polar solvent and of the stoichiometric amount of an acid acceptor, at a temperature range of from about 0 C. to about 100 C. It is preferred that the reaction temperature be in the range of 50 C. to C.

Examples of suitable solvents are ketones, such as acetone, methyl ethyl ketone, diethyl ketone and as examples representing other types of solvents, dimethyl formamide, acetonitrile and nitromethane. I

As acid acceptor two further equivalents of the imidazole derivative may be used: however, the corresponding quantity of one of the conventional tertiary amines is preferably used, such as triethylamine, dimethylanilin, N,N-dimethyl-benzylamine and the like.

The starting materials used for the process of the present invention, i.e. the diphenyl-dihalornethanes of the formula (2) and the imidazole derivatives of the formula (3) are known or can be obtained according to methods and/ or procedures per se known. I

3-chloro-4-methoxy-diphenyldichloromethane 4-chloro-4'-methoxy-diphenyldichloromethane 2-methyl-4'-methoxy-diphenyldichloromethane 3-methyl-4-methoxy-diphenyldichloromethane 4-methyl-4'-methoxy-diphenyldichloromethane 2- fluoro-4-methylthio-diphenyldichloromethane 3-fluoro-4-methylthio-diphenyldichloromethane 4-fiuoro-4'-methylthio-diphenyldichloromethane 2-chloro-4-methylthio-diphenyldichloromethane 3-chloro-4'methylthio-diphenyldichloromethane 4-chloro-4-methylthio-diphenyldichloromethane 2,4-dichloro-4-methylthio-diphenyldichloromethane 2,5-dichloro-4'-methylthio-diphenyldichloromethane 3 ,4-dichloro4-methylthio-diphenyldichloromethane 2,4-dichloro-4-methoxy-diphenyldichloromethane 2,5-dichloro-4-methoxy-diphenyldichloromethane 3,4-dichloro-4-methoxy-diphenyldichloromethane 4-ethylthio-2-chloro-diphenyldichloromethane 4-ethylsulphonyl-2-chloro-diphenyldichloromethane The following examples are representative of compounds of the formula (3);

imidazole 2-rnethy1imidazole Z-ethylimidazole Z-phenylirnidazole 4, 5 -phenylimidazole 4,5-diphenylimidazole benzimidazole Salts of compounds of the formula 1) may be converted into their corresponding salts by techniques per se known. For example, 0.2 mol of a bis-imidazolyl-bisphenylmethane may be dissolved with heating in acetonitrile, followed by the addition of 0.22 ml. D,L-1actic acid. The residue remaining after the solvent has been distilled off may be made to crystallize by covering it, after filtration, With a layer of ether; the crystalline product may be Washed with ether and dried.

The hydrochlorides are expediently obtained by introducing hydrogen chloride into the solution of the imidazole derivative, for example, in carbon tetrachloride.

The following table shows examples of the compounds of the invention:

M.P., C. (a) Bis-imidazolyl-bis-phenylmethane 190 (b) Bis-imidazolyl 4 chlorophenyl phenylmethane 140 (c) Bis imidazolyl 4 fiuorophenyl phenylmethane 130 (d) Bis imidazolyl 2,4 difluoro diphenylmethane 129 (e) Bis-imidazolyl 2 chlorophenyl phenylmethane 143 (f) Bis-imidazolyl 3 chlorophenyl phenylmethane 118 (g) Bis-imidazolyl 4 cyanophenyl phenylmethane 125 (h) Bis (2 methylimidazolyl) 4 chlorophenylphenylemthane 215 The compounds and salts of the formula (1) can be used, inter alia, in the form of an aqueous emulsion, suspension or solution. It is also possible to use the aqueous solutions of the salts of the above compounds.

The invention is illustrated by the following Examples.

EXAMPLE 1 Bis-imidazolyl-4-chlorophenyl-phenylmethane To a solution of 27.2 g. (0.4 mol) imidazole and 40.4 g. (0.4 mol) triethylamine in 300 ml. acetonitrile there are added dropwise 54 g. (0.2 mol) ,4-chlorophenyl-phenyl-dichloromethane. The triethylamine hydrochloride formed starts to separate at room temperature. The mixture is heated at C. for 12 hours to complete the reaction. After cooling, the reaction mixture is stirred with 500 m1. benzene and washed with water until free of salt. The benzene solution is dried over anhydrous sodium sulphate, filtered and concentrated by evaporation; after recrystallisation of the crude product from acetonitrile, there result 41 g. of pure bis-imidazolyl-4- chlorophenyl-phenylmethane of m.p. 140 C.

C H ClN (mol. weight 334.5). Calculated (percent) C, 68.0; H, 4.5; Cl, 10.6; N, 16.7. Found (percent): C, 68.0; H, 4.8; Cl, 10.7; N, 16.9.

The same compound is obtained when, as starting compound, the dichloromethane compound is replaced by 4- chlorophenyl-phenyl-dibromomethalue or the corresponding diiodine compound.

EXAMPLE 2 Bis-imidazolyl-4-fluorophenyl-phenylmethane Into a solution of 29.4 g. (0.43 mol) imidazole and 43.7 g. (0.43 mol) triethylarnine in 300 ml. acetonitrile there are added drop-wise 55 g. (0.21 mol) 4-fluorophenylphenyl-dichlorornethane. Separation of the triethylammonium chloride formed begins at room temperature. The mixture is heated at 80 C. for 12 hours to complete the reaction. After cooling, the reaction mixture is stirred with 500 ml. benzene and Washed with water until free of salt. The benzene solution is dried over anhydrous sodium sulphate, filtered and evaporated; after recrystallisation of the crude product from acetonitrile there result 42 g. pure bis-imidazolyl-4-fluorophenyl-phenylmethane of m.p. C.

C H FN (mol. weight 318). Calculated (percent): C, 71.8; H, 4.7; F, 6.0; N, 17.6. Found (percent): C, 71.7; H, 4.9; F, 6.0; N, 17.6.

The following compounds of the formula (4) are prepared in a manner analogous to that set" forth in Example 2 by reacting the appropriate diphenyl-dichloromethane from the list in columns 3, 4 and 5, With the appropriate imidazole set forth in column 5.

EXAMPLES 3-9 The following compounds of the formula (5) are prepared in a manner analogous to that set forth in Example 2 by reacting the appropriate diphenyl-dichloromethane from the list in columns 3, 4 and 5, with the appropriate imidazole set forth in column 5.

7 EXAMPLES 10-1s X N l Y X Y M.P. C.

4-F 129 4-F 196 4-01 183 4-C1 198 4-NO2 198 4-CN 190 The following compounds of the formula (6) are prepared in a manner analogous to that set forth in Examples 1 and 2 by reacting the appropriate diphenyl-dichloromethane from the list in columns 3, 4 and 5, with the appropriate imidazole set forth in column 5.

EXAMPLES 1 6-3 4 THERAPEUTIC UTILITY I. Effectiveness in vitro against human-pathogenic fungi (1) T richophyton mentagrophytes:

Compound (a): (47/ ml. fungistatic Compound (b): 4' /ml. Compound 4 y/ml. Compound (d): 4v/ml. Compound (e): 4'y/ml. Compound (f): 4'y/ml. Compound (g): 40'y/ml.

(2) Candida albicans: 1007/1111.

(3) Penicillium c0m.: 20'y/ml.

(4) Aspergillus niger: 20y/m1.

(5) Microsp. feL: 40'y/ml.

The test medium was Milieu depreuve according to Sabouraud, incubation temperature: 28 C.

II. In vivo activity Taking as example white mice infected i.v. with Candida albicans and Aspergillus fumigatus, the new compounds [c.g. (a) to (h)], given orally in doses of 50-1'00 mg/kg. body weight once or twice daily over 5 days, show good curative effects. Dependent upon the dosage, the rate of survival of the animals thus treated amounted to 50 to of the untreated control animals 0 to 10%.

With the same dosage scheme and a therapy duration of 8 to 10 days, the development of dermatomycoses caused by Trichophyton and Microsporium species can be inhibited in mice and guinea pigs in an average of 70% of the infected animals; in comparison with the untreatedcontrol group, the infection proceeds in the remaining 30% midly and adheres for only a short period of time.

The topically-therapeutic application in the form of ointments and tinctures with a 1% content of active ingredient leads in kuinea pigs infected with dermatophytes to healing of the mycosis within 6 to 8 days post infection whereas in untreated control animals the dermatomycosis has an average duration of 28 to 31 days.

Similar results are obtained when, instead of the compounds (a) to (h), the other new compounds or salts are used.

Of special interest for practical use are the compounds which are unsubstituted on the imidazole ring, but which may be substituted in one phenyl moiety by a halogen atom (preferably chlorine, fluorine, in the 0, mor pposition, i.e. 2-, 3- or 4-positi0n) as well as their salts with hdyrochloric acid, lactic acid or salicyclic acid.

It is particularly envisaged that the compounds of the present invention may be used in the following manner:

(a) In human medicine:

1. Dermatomycoses caused by fungi of the species Trichophytes, Microporium, Epidermophytes, Aspergillus,, Candida albicans, and other yeasts,

2. Organomycoses caused by yeasts, mould fungi and dermatophytes.

(b) In veterinary medicine: Dermatomycoses and organomycoses caused by yeasts, mould fungi and dermotophytes. The therapeutical application can be effected orally of parenterally as well as locally in the form of solutions (e.g. dimethyl sulphoxide/glycerol/water 2:2:6), alcohol, preferably ethanol and isopropanol, buffer solutions, powders, dreams, ointments and tablets. For topical application preferably a concentration of about from 0.5 to 10% of effective ingredient is used.

For humans the dosage amounts on average to between about 50 and about 100 mg./kg. body weight, preferably 50 to about 80 mg./kg. body weight, at intervals of up to 12 hours for the duration of about 8 to about 10 days.

However, it may of course be found desirable in some cases to deviate from the quantities indicated here, not only depending on the method of application, but also on possible variations in individual reactions to the compound or the kind of formulation and on the time or the interval at which it is administered. It may thus be possible to manage with less than the abovementioned minimum amount in some cases, whereas in other cases the indicated upper limit may have to be exceeded. If larger quantities are administered, it may be advisable to distribute these in several individual closes over the day.

The compounds of the present invention may be used as such or in combination with pharmaceutically acceptable nontoxic inert diluents or carriers. Suitable forms of application, in combination with various inert carriers, are the following: tablets, capsules, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers comprise solid diluents or fillers, a sterile aqueous medium as well as non-toxic organic solvents and the like. Tablets and the like intended for oral use may, of course, be provided with sweetening additives and other conventional substances. The therapeutically active compound should generally be present at a concentration of about 0.5 to percent by weight of the total mixture, in quantities which are suflicient to achieve the dosage range mentioned above.

For oral application, the tablets can obviously also contain additives, such as sodium citrate, calcium carbonate and dicalcium phosphate together with various other additives, such as starch, preferably potato starch, and the like, and binding agents, such as polyvinyl-pyrrolidone, gelatin and the like. Lubricants, such as magnesium stearate, sodium lauryl sulphate and talc may also be used concurrently for the production of the tablets. In the case of aqueous suspensions and/or elixirs which are intended for oral use, the active substance may be provided with various agents to improve the flavour, colouring substances, emulsifiers and/or with diluents, such as water, ethanol, propylene glycol, glycerol and similar compounds or combinations.

For parenteral application, solutions of the active substances in sesame or peanut oil, or in aqueous propylene glycol or N,N-dimethyl formamide can be employed as well as sterile aqueous solutions in the case of watersoluble compounds. Aqueous solutions of this kind should bebuifered in theusual manner if necessary; furthermore, the liquid diluent should be rendered isotonic from the start by the addition of the necessary amount of salt or glucose. Such aqueous solutions are particularly suitable for intravenous, intramuscular and intraperitoneal injections.

Sterile aqueous media of this kind are prepared in known manner.

In mice, rats, rabbits, dogs and cats the LD of the compounds mentioned above ranges from about 500 and 1000 mg./kg. body weight when orally administered.

The present invention also includes pharmaceutical compositions comprising-one or more compounds as hereinbefore described as the active ingredient in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier.

The present invention further provides a medicament inunit dosage form which comprises at least one of the compounds hereinbefore described either alone or in combination with a pharmaceutically acceptable inert diluent or carrier. The medicament may include a protective envelope containing the active compound and if used the diluent or carrier.

The term medicament in dosage unit form" as used in the present specification means a medicament as defined above in the form of discrete portions each containing a unit dose, or a multiple or sub-multiple of a unit dose of the active compound or compounds. Such portions may, for example, be in monolithic coherent form, such as tablets, suppositories, pills or dragees; in wrapped or concealed form, such as wrapped powders, cachets, sachets, or capsules; in ampoules, either free or as a sterile solution suitable for parenteral injection; or in any other form known to the art.

Besides the antimycotic activity the compounds show an activity against pathogenic protozoa, e.g. Trypanosoma, Trichomonas, Entamoeba histolytica, malaria parasites, Toxoplasma and against bacteria, e.g. Staphylococci, Streptococci, Klebsiella, E. coli.

Further the compounds activate the granulation in wound healing and show a hypocholesterinaemic activity.

What is claimed is:

1. A pharmaceutical composition useful for treating fungal infections pathogenic to humans or animals which comprises an antifungally eifectve amount of a compound of the formula:

-N 1.1 @t@ X.., /N\ R1 Y Li wherein R is hydrogen, methyl or ethyl,

X and Y are the same or different and are chloro, bromo or tfluoro,

m is 0, 1 or 2, and

nis1or2, ornis0,1or2,andmis1or2,

or a pharmaceutically acceptable non-toxic salt thereof, in combination with a pharmaceutically acceptable, nontoxic, inert diluent or carrier.

2. A pharmaceutical composition according to claim 1 wherein R is hydrogen.

3. A pharmaceutical composition according to claim. 2 wherein m is 1 and n is O.

4. A pharmaceutical composition according to claim 2 wherein m is 2 and n is O.

5. A pharmaceutical composition according to claim 2 wherein m is 1 and n is 1.

6. A pharmaceutical composition. according to claim 2 wherein X is chloro, m is 2 and the chloro substituents are in the 2 and 5 positions.

7. A pharmaceutical composition. according to claim 5 wherein X is Z-fluoro and Y is 4-fiuoro.

8. A pharmaceutical composition according to claim 5 wherein X is 4-fiuoro and Y is 4-flu oro.

9. A pharmaceutical composition according to claim 5 wherein X is 4-fluoro and Y is 4-chloro.

10. A pharmaceutical composition according to claim 5 wherein X is 4-chloro and Y is 4-chloro.

11. A pharmaceutical composition according to claim 1 wherein R is methyl, X is 4-fluoro, m is 1 and n is 0.

12. A pharmaceutical composition according to claim 1 wherein R is methyl, X is 2-chloro, m is 1 and n is 0.

13. A pharmaceutical composition according to claim 1 wherein R is methyl, X is 3-chloro, m is 1 and n is 0.

14. A pharmaceutical composition according to claim 1 wherein R is ethyl, X is 4-fiuoro, m is 1 and n is 0.

15. A pharmaceutical composition according to claim 1 wherein R is ethyl, X is 4-chloro, m is 1 and n is 0.

16. A pharmaceutical composition according to claim 1 wherein R is ethyl, X is 4-bromo, m is 1 and n is 0.

17. A pharmaceutical composition according to claim 1 wherein R in methyl, X is Z-fluoro, m is 1, Y is 4-fiuoro, and n is 1.

18. A pharmaceutical composition according to claim 1 wherein R is methyl, X is 4 fiuoro, m is 1, Y is 4-fluoro, and n is 1.

19. A pharmaceutical composition according to claim -1 wherein R is methyl, X is 4-fluoro, m is 1, Y is 4-chloro,

and n is 1.

20. A pharmaceutical composition according to claim 1 wherein R is methyl, X is 4-chloro, m is 1, Y is 4-chloro, and n is 1.

21. A pharmaceutical composition according to claim 1 wherein R is ethyl, X is 2-fluoro, m is 1, Y is 4-fluoro and n is 1.

22. A pharmaceutical composition according to claim 1 wherein R is ethyl, X is 4-fluoro, m is 1, Y is 4-chloro and n is 1.

23. A pharmaceutical composition according to claim 1 wherein R is ethyl, X is 4chloro, m is 1, Y is 4-chloro and n is 1.

24. A pharmaceutical composition according to claim 2 wherein the compound is bis-imidazolyl-4-chlorophenylphenylmethane.

25. A pharmaceutical composition according to claim 2 wherein the compound is bis-imidazolyl-4fluorophenylphenylmethane.

26. A pharmaceutical composition according to claim 2 wherein the compound is bis-imidazolyl-2,4'-difiuorodiphenylmethane.

27. A pharmaceutical composition according to claim 2 wherein the compound is bis-imidazolyl-2-chlorophenylphenylmethane.

28. A pharmaceutical composition according to claim 2 wherein the compound is bis-imidazolyl-3-chlorophenylphenylmethane.

29. A pharmaceutical composition according to claim 1 wherein the compound is bis-(2-methylimidazolyl)-4- chlorophenyl-phenylmethane.

30. A pharmaceutical composition according to claim 1, in oral administration form.

31. A pharmaceutical composition according to claim 1 in topical application form.

32. A pharmaceutical composition according to claim 31 which contains from 0.5% to concentration of active agent.

33. A pharmaceutical composition according to claim 31 wherein in the concentration of active agent is about 1%.

34. A method for treating fungal infections pathogenic to humans or animals which comprises administering to a human or animal in need of such treatment an antifungally efiective amount of a compound of the formula tit. Q-iQ wherein R is hydrogen, methyl or ethyl,

X and Y are the same or dilferent and are chloro, brorno or fluoro,

m is 0, 1 or 2, and

nis1or2,ornis0,1or2,andm-is1or2,

or a pharmaceutically acceptable non-toxic salt thereof.

35. A method according to claim 34 wherein R is hydrogen.

36. A method according to claim 35 wherein m is 1 and n is 0.

37. A method according to claim 35 wherein m is 2 and n is 0.

38. A method according to claim 35 wherein m is 1 and n is 1.

39. A method according to claim 37 wherein X is chloro, m is 2 and the chloro substituents are the 2 and 5 positions.

40. A method according to claim 38 wherein X is 2 fiuoro and Y is 4-fluoro.

41. A method according to claim 38 wherein X is 4-fluoro and Y is 4-fluoro.

42. A method according to claim 38 wherein X is 4-fluoro and Y is 4-chloro.

43. A method according to claim 38 wherein X is 4-chloro and Y is 4-chloro.

44. A method according to claim 34 methyl, X is 4-fluoro, m. is 1 and n is 0.

45. A method according to claim 34 methyl, X is 2-chloro, m. is 1 and n is 0.

46. A method according to claim 34 methyl, X is 3-chloro, m is 1 and n is 0.

47. A method according to claim 34 ethyl, X is 4-fluoro, m is 1 and n is 0.

48. A method according to claim 34 ethyl, X is 4-chloro, m is 1 and n is 0.

49. A method according to claim 34 ethyl, X is 4-bromo, m is 1 and n is 0.

50. A method according to claim 34 wherein R methyl, X is 2-fluoro, m is 1, Y is 4-fluoro, and n is 1.

51. A method according to claim 34 wherein R methyl, X is 4 fluoro, m is 1, Y is 4-fluoro, and n is 1. 52. A method according to claim 34 wherein R methyl, X is 4-fiuoro, m is 1, Y is 4-chloro, and n is 1.

53. A method according to claim 34 wherein R methyl, X is 4-chloro, m is 1, Y is 4-chloro, and n is 1. 54. A method according to claim 34 wherein R ethyl, X is Z-fiuoro, m is 1, Y is 4-fluoro and n is 1.

55. A method according to claim 34 wherein R ethyl, X is 4-fluoro, m is 1, Y is 4-chloro and n is l.

56. A method according to claim 34 wherein R ethyl, X is 4-chloro, m is 1, Y is 4-chloro and n is 1.

57. A method according to claim 35 wherein the compound is bis-imidazolyl-4-chlorophenyl-phenylmethane.

58. A method according to claim 35 wherein the compound is bis-imidazolyl-4fluorophenyl-phenylmethane.

59. A method according to claim 35 wherein the compound is bis-imidazolyl-2,4-difluoro-diphenylmethane.

60. A method according to claim 35 wherein the compound is bis-imidazolyl-2-chlorophenyl-phenylmethane.

61. A method according to claim 35 wherein the compound is bis-imidazolyl-3-chlorophenyl-phenylmethane.

62. A method according to claim 35 wherein the compound is bis-'(2-methylimidazolyl)-4-chlorophenyl-phenylmethane.

63. A method according to claim 34 wherein said administration is oral.

64. A method according to claim 34 wherein said administration is topical.

65. A method according to claim 35, wherein X is 4-bromo, m is 1 and n is 0.

wherein R is wherein R is wherein R is wherein R is wherein R is wherein R Fournari et al., Bul. Soc. Chim. France, June 1968, pp. 24382446.

Tolkmith et al., Science, vol. 158, pp. 1462-1463.

JEROME D. GOLDBERG, Primary Examiner UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,824,310 Dated July 16, 1974 Inventoflg) Erik Regal, Karl Heinz Buchel and Manfred Plempel It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In column 1, preceding the Abstract of the Disclosure, insert:

-- Foreign Application Priority Data .November 5, 1968 Germany P 18 06 995.9

Signed and sealed this 6th day of May 1975 (SEAL) Attest:

C. MARSHALL DANN RUTH C. MASON Commissioner of Patents Attesting Officer and Trademarks FORM PC4050 (10-69) USCOMM-DC SOUS-P60 I no. will!!!" ammo omcl nu o-su-aa. 

